Real-World Data on Prognostic Factors for Overall

Survival in EGFR-Mutant Non-Small-Cell Lung Cancer

Patients with Brain Metastases.

Xiaoqing Yu1, Yun Fan2

1Department of Second Clinical Medical College, Zhejiang Chinese Medical

University, Hangzhou, Zhejiang, People's Republic of China.

2 Technology on Thoracic Oncology (esophagus, lung), Zhejiang Caner Hospital,

Hangzhou, 310022, Zhejiang, People’s Republic of China

Correspondence to: Dr. Yun Fan, Key laboratory Diagnosis and Treatment

Technology on Thoracic Oncology (esophagus, lung), Zhejiang Caner Hospital, No 1,

East Banshan Road, Gongshu District, Hangzhou, 310022, Zhejiang, People’s

Republic of China

Tel +86 571 8812 2191

Fax +86 571 8812 2589

Email fanyun_zjcc@163.com

Abstract

Background:

With the wide application of epidermal growth factor receptor-tyrosine kinase

inhibitors (EGFR-TKIs), the survival of EGFR-mutant non-small-cell lung cancer

(NSCLC) patients with brain metastasis (BM) has been significantly improved.

However, prognosis analysis for patients with EGFR mutation and BM is still lacking,

and the prognostic factors remain to be determined.

Materials and methods:

A total of 746 NSCLC patients with BM were identified between January 2013 and

December 2016 at our institution. Overall, 261 patients harboring EGFR mutation and

meeting the inclusion criteria for the study were enrolled. Exclusion criteria included

KPS<50, diagnosed with BM during treatment with EGFR-TKIs, or insufficient

follow-up. Overall survival (OS) was measured from the date of brain metastases.

Independent prognostic factors were confirmed using a Cox regression model.

Results: The median follow-up time for these patients was 32.7 months (95% CI,

23.5-41.9). The median OS after development of brain metastases was 23.0 months

(95% CI, 20.01-25.99). By univariate analysis, significantly shorter OS was noted in

patients older than 65 years (p=0.025), KPS <70 (p=0.003), presence with ECM

(p=0.00), without intracranial local treatment (p=0.000), and without chemotherapy

(p=0.001). There was no difference in OS with respect to EGFR mutation type and

number of BM (p=0.343, p=0.729, respectively). The Cox proportional hazards

regression model revealed that performance status (KPS<70, p=0.010), ECM

(p=0.001), receiving intracranial local treatment (p=0.005) and chemotherapy

(p=0.005) were independent prognostic factors for OS, while age was not (p=0.087).

Patients with higher diagnosis-specific graded prognostic assessment (DS-GPA) and

Lung-molGPA scores corresponded to better prognosis (p=0.000).

Conclusion: This retrospective analysis demonstrated that performance status

(KPS≥70), absence of ECM metastases, administration of local treatment and

chemotherapy were associated with superior OS in patients with EGFR-mutant

NSCLC who developed BM. The DS-GPA and Lung-molGPA indexes still applied to

NSCLC patients with mutant genotypes and BM.

Keywords: Non-Small-Cell Lung Cancer, Brain Metastases, Prognostic

Factors，Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors

Introduction

Brain metastasis (BM) has become a leading cause of death from non-small-cell lung

cancer (NSCLC), with an incidence of approximately 25-40%[1, 2]. As systemic

therapies improve, NSCLC patients live longer and are thus at an increased risk for

brain metastases. For patients harboring epidermal growth factor receptor (EGFR)

mutations, the incidence of BM is up to 50%, which seriously affects patient

prognosis [3]. The reported frequency of somatic EGFR mutations varies from 30% to

50% among East Asians to approximately 10% among Caucasians[4]. Currently,

EGFR-tyrosine kinase inhibitor (TKI) is the standard first-line treatment for patients

with advanced, recurrent, or metastatic NSCLC harboring an EGFR mutation [5].

Preclinical data have demonstrated that gefitinib, icotinib and erlotinib can penetrate

the blood-brain barrier (BBB) at concentrations adequate for initiating antitumor

activity[6, 7]. The reported cerebrospinal fluid (CSF)/plasma concentrations of the

first-line EGFR TKIs are approximately 0.6-2.5%[8-10]. Many retrospective and

prospective studies have confirmed that EGFR TKIs have significant intracranial

activity[9, 11]. A large phase 3, randomized controlled trial (BRAIN) reported by Wu

et al. examined the efficacy of icotinib and whole-brain irradiation (WBI) in primary

diagnosed NSCLC patients with EGFR mutations and at least three metastatic brain

lesions[12]. The results showed icotinib has superior iPFS, PFS and ORR over WBI

in EGFR-mutant advanced NSCLC with BM and has a well-tolerated safety profile.

Therefore, the therapeutic status of EGFR TKIs in EGFR-mutant patients with BM

has been confirmed. However, historically, brain metastases have been treated with

surgical resection, stereotactic radiosurgery (SRS), or whole-brain radiotherapy

(WBRT), either alone or in combination. Recently, a retrospective study reported in

Journal of Clinical Oncology by Magnuson and his colleagues demonstrated that the

use of upfront EGFR-TKI, and deferral of radiotherapy, is associated with inferior

overall survival (OS) in patients with EGFR-mutant NSCLC who develop brain

metastases[5]. Therefore, despite the availability of various treatment options in this

group of patients with BMs, including EGFR-TKIs, WBRT, and SRS, the optimal

treatment combination or sequence has been unclear. BM is a complex and

genetically heterogeneous population. Extensive efforts have focused on predicting

outcomes for BM patients. The prognostic indexes have been widely applied in

clinical practice, such as the Graded Prognostic Assessment (GPA) and the Disease-

Specific GPA (DS-GPA). However, these indexes were mostly based on BM patients

with unknown genetic status. Recently, an update of the DS-GPA using molecular

markers (Lung-molGPA) was proposed by Paul W. Sperduto, incorporating gene

alteration data into the DS-GPA. However, the prognostic value of the Lung-molGPA

models for patients with EGFR mutation remains undetermined. The recent revolution

in the treatment of patients with predictive biomarkers brought about the significant

improvement of survival outcomes; thus, we sought to describe outcomes for patients

with NSCLC and EGFR mutations and to identify prognostic factors for survival in a

real-world population of EGFR-mutant NSCLC patients with BM that can be used to

appropriately tailor treatment strategies. We also wanted to evaluate the therapeutic

value and the prognostic effect of intracranial local therapy, chemotherapy and

comprehensive treatments on patient survival. Meanwhile, we evaluate the prognostic

value of the DS-GPA and Lung-molGPA indexes.

Materials and methods

Patients and Populations

In this retrospective study, all patients aged 18 years or older with a diagnosis of

NSCLC and with magnetic resonance imaging (MRI) confirmed BM diagnoses at our

institution between January 2013 to December 2016 were identified. Other eligibility

criteria included the following: harboring EGFR mutations and treatment with EGFR

TKIs. Exclusion criteria included the following: KPS<50, diagnosed with BM during

treatment with EGFR TKIs, and loss to follow-up. Baseline clinical characteristics

were recorded by retrospective chart review, including age at diagnosis of BM, sex,

smoking history, KPS, tumor histology, number of BM, ECM, whether the patient

was symptomatic from BM and synchronous BM, type of EGFR mutation,

intracranial local therapy delivered, and chemotherapy that was delivered. Patient

follow-up by telephone was done until April 2018. Treatment response was evaluated,

and survival data were collected and analyzed. This investigation was approved by the

Zhejiang Center Hospital Ethics Committee.

Assessment

MRI scans of the brain, along with positron emission tomography-computed

tomography (CT) scans of the chest, were reviewed every 2 months. Tumor response

to treatment was evaluated based on Response Evaluation Criteria in Solid Tumors

version 1.1[13]. The primary outcome of this study was OS, defined as the duration

between the diagnosis of BM and the time of death (all causes).

Statistical Analysis

Patient OS was assessed using the Kaplan-Meier method. The log-rank test was used

for comparison of survival curves of different characteristics. Prognostic factors for

OS were analyzed by univariate and multivariate analyses. Variables with p<0.1 were

added to the final multivariate Cox regression model. The hazard ratio (HR) and 95%

confidence interval (CI) were calculated for all variables in the regression model.

Statistical significance was set at p<0.05. All statistical analyses were performed

using SPSS software, version 20.0 (SPSS Inc., Chicago, IL, USA).

Results

Patient characteristics

From January 1, 2013, to December 31, 2016, a total of 746 patients were diagnosed

with NSCLC with BM at Zhejiang Cancer Hospital. Of these patients, 269 EGFR-

mutant patients had been treated with EGFR TKIs after the diagnosis of BM. After

excluding those who met the exclusion criteria, 261 patients were enrolled in the

study (Fig. 1). The median follow-up time for these patients was 32.7 months (95% CI

23.5-41.9). The median age was 54 years (range 30-79 years). The patients were

predominantly younger than 65 years old (≤65 years old, 85.8%), female (59.4%),

with a KPS score≥70 (71.6%), histology of adenocarcinoma (92.0%), lower number

of BM (number of BM lesions≤3, 67%), without ECM (55.2%), without symptomatic

BM (56.3%), with synchronous BM (72.4%), receiving local therapy (74.7%) and

chemotherapy (56.3%). All patients were stratified according to the criteria of DS-

GPA and Lung-molGPA. Overall, 42 patients (16.1%) had a DS-GPA score of 0-0.5,

102 patients (41.0%) were 1-1.5, 86 patients (33.0%) were 2-2.5, and 26 patients

(10.0%) were more than 3. For the Lung-molGPA index[3], 7 patients (2.7%) were 0-

1, 71 (27.2%) were 1.5-2, 125 (47.9%) were 2.5-3, and 58 (22.2%) were above 3.5.

These EGFR-mutant cases included 138 (52.9%) exon 19 deletion, 90 (34.5%) L858R

mutation, and 33 (12.6%) other EGFR mutations (including the presence of T790M

mutation during treatment and other uncommon mutations). Due to medical insurance

limitations, icotinib was not covered by Zhejiang Medicare until June 2016, whereas

gefitinib and erlotinib were not covered until September 2017. Therefore, 38.8%

patients received chemotherapy as first-line treatment in this study. Up to 69.3%

patients had received icotinib in our study. Platinum doublet-chemotherapy was the

most common chemotherapy regimen. The patient characteristics at baseline are

detailed in Table 1.

Treatment

Within the patients who received intracranial local therapy, 137 (70.2%) received

WBRT, 37 (19.0%) received SRS or surgical resection, and 21 (10.8%) had a

combination of the above. There were 161 (61.7%) patients who received EGFR TKIs

as first line treatment. Among the 161 patients, 105 (65.2%) were treated with

icotinib, 38 (23.6%) with gefitinib, and 18 (11.2%) with erlotinib. There was no

difference in OS between different EGFR TKIs (p=0.087). Additionally, 117 (72.7%)

of these 161 patients received radiotherapy (RT), 86 received upfront RT (with an

interval between RT and TKI treatment ≤1 months), and 31 received deferral RT. We

found no significant difference in OS between the two groups (p=0.395).

Postprogression Treatment

It should be noted that osimertinib did not enter the Chinese market until April 2017;

hence, only 24 patients received osimertinib after the progression of first-line EGFR

TKIs. We found that patients treated with osimertinib achieved a survival benefit from

its use (p=0.011).

OS and Prognosis

The median OS was 23.0 months (95% CI 20.0–26.0, Fig. 2). By univariate analysis,

significantly shorter OS was noted in patients older than 65 years (p=0.025), KPS <70

(p=0.003), and patients with ECM (p=0.00). Patients who received chemotherapy

were more likely to have longer OS than those who did not (28.0 vs 16.5, p=0.01).

Meanwhile, patients who received local therapies also had longer OS than those who

did not receive local therapies (24.9 vs 16.0, p=0.00). In addition, we found patients

who revived SRS or surgical resection tended to have longer OS than those who

underwent other local therapy methods (SRS or surgical resection 34.4 vs WBRT 23.2

vs combination 19.0), though it didn’t reach the statistical significance (p=0.067).

There was also no difference in the patients respect to sex, smoking history, EGFR

mutation type, number of BM. In multivariate analyses using multiple Cox

proportional hazards models, we observed that performance status (KPS<70,

p=0.010), extracranial metastases (ECM) at time of brain metastases (p=0.001),

receiving intracranial local treatment (p=0.005) and chemotherapy (p=0.005) were

independent prognostic factors for OS, while age was not (p=0.087). As for the

prognostic index, survival by DS-GPA and Lung-molGPA group showed excellent

separation between groups (p=0.000; p=0.000; Fig. 3) The survival times for all

patients with DS-GPA scores of 0-0.5, 1.0-1.5, 2.0-2.5, and more than 3 were 16.0,

17.7, 27.0 and 42.0 months, respectively. In addition, survival times for patients with

Lung-molGPA scores of 0-1.0, 1.5-2.0, 2.5-3.0, and more than 3.5 were 15.0, 16.0,

23.7 and 32.0 months, respectively. Taken together, both the DS-GPA and Lung-

molGPA models predicted the prognosis of NSCLC patients with BM (P=0.000).

However, the Lung-molGPA model did not show further superiority of its predictive

effect. In multivariate analyses using multiple Cox proportional hazards models, we

observed that performance status (KPS≥70; HR 0.639, 95% CI 0.455-0.897, p=0.010),

ECM (HR 1.733, 95% CI 1.256-2.391, p=0.001), local therapy (HR 0.607, 95% CI

0.430-0.857, p=0.005) and chemotherapy (HR 0.629, 95% CI 0.455-0.870, p=0.005)

were independent prognostic factors for OS, while age was not (HR 1.436, 95% CI

0.949-2.172, p=0.087; Table 2, Fig. 4).

Discussion

In this study, we found that KPS, absence of ECM, receiving intracranial local therapy

and the administration of chemotherapy were independent prognostic factors for OS

in patients harboring an EGFR mutation and brain metastases, in real-world practice.

While age, number of BM and EGFR mutation type showed no impact on survival.

We also found that the sequence of RT and EGFR TKIs had no significant effect on

prognosis. The DS-GPA and Lung-molGPA indexes were still valid in predicting the

prognosis of EGFR-mutant patients with BM, but the Lung-molGPA index did not

show further superiority in NSCLC patients with BM and clear gene status.

Extracranial metastases as a prognostic predictor has been reviewed previously.

Regardless of the Recursive Partitioning Analysis (RPA) or the DS-GPA index or any

other prognostic index, ECM has always been an independent prognosticator

influencing survival and is most often the strongest one[14-17]. In our study, ECM

was once again confirmed to be prognostic. It is reasonable to assume that patients

with ECM would live shorter periods than those without ECM. The underlying

mechanism could be that patients with ECM once had a heavy disease burden.

Treatments for these patients should be both intracranial and extracranial, which

might be the possible reason for their worse prognosis. As Kocher et al. pointed out,

the presence of ECM may also influence survival by reseeding the brain parenchyma,

thus forming another potential source of new brain metastasis, as indicated by the

presence of multiple extracranial metastases[18]. Meanwhile, patients with good

control of ECM-associated activities have a certain curative rate and can benefit more

from local treatment.

The number of BM has been reported to be a poor prognostic factor in NSCLC. Our

study, however, found that the number of BM was not associated with survival. This

finding may imply that the number of BM is not a reliable prognostic factor in the

setting of EGFR mutations and TKI therapy. Previous database analysis of the

prognostic indexes included EGFR wild-type group, and this inclusion may have

affected the accuracy of prognosis for EGFR-mutant patients[3, 15, 17].We assume

that TKIs have a good control of intracranial lesions in patients with EGFR mutations

and BM. Therefore, the number of BM may not influence the efficacy of TKIs.

In our analysis of di erent EGFR mutation subgroups, we found EGFR mutation typeff

had no impact on OS. Median OS of patients with exon 19 deletion, L858R mutation

and other EGFR mutations in our study was 23.6 months, 19.7 months and 27.0

months, respectively (p=0.343). Former studies have found exon 19 deletion achieved

better OS than L858R mutation in NSCLC patients receiving EGFR-TKI

treatments[4, 19, 20]. A similar result was also found in EGFR-mutant patients with

BM[6]. Nevertheless, there were reports that indicated that the type of EGFR

mutation was not predictive for the development of brain metastases or the survival of

patients[21]. A number of studies have reported that the efficacies of EGFR-TKIs are

distinct among di erent mutant subtypes. However, most patients with BM would beff

willing to undergo intensification therapy for intracranial lesions. This result could be

the reason that, in our study, EGFR mutation type had no apparent impact on the

survival of patients with BM.

A series of studies evaluating the use of cranial local therapies in patients with BM

has been performed and suggests a survival benefit from local therapy. In our study,

we noted that the administration of local therapy can significantly improve survival

and was a prognostic predictor. In the current era of targeted therapy, EGFR TKIs

alone have demonstrated activity against intracranial disease in EGFR-mutant

NSCLC[11, 22, 23]. In addition, a systematic review and meta-analysis of 12 studies

found that, relative to treatment with TKIs alone, cranial radiotherapy followed by

EGFR TKIs improves intracranial control and survival outcomes in EGFR-mutant

NSCLC with BM [24]. Multiple studies have shown patients with EGFR mutation to

be highly radiosensitive in both the preclinical and clinical settings, thereby making

the ablation of BM a distinct possibility[25, 26]. It was previously reported that local

control rates of SRS in the treatment of EGFR-mutant brain metastases had reached

100% and 93%[25, 27]. Another multi-institutional analysis also revealed the impact

of RT followed by EGFR TKIs on patient outcomes was most pronounced in patients

with a more favorable prognosis (dsGPA,2-4)[5]. For patients with good DS-GPA

scores, more active and reasonable intracranial local treatment is recommended.

In the subgroup of patients who received EGFR TKIs as first-line treatment, no

significant difference in OS was noted between patients who received upfront RT and

those who did not (p=0.395), which is a different result than reported in previous

studies. A retrospective study found that the use of upfront EGFR-TKI, and deferral of

RT, would result in inferior survival in patients with EGFR-mutant NSCLC who

develop BM[28]. Extensive efforts have focused on the optimal sequence of RT for

BM patients. Magnuson et al. also noted significantly worse survival in those who had

delayed brain RT, regardless of whether it was SRS or WBRT[5, 29]. However, this

finding needs to be interpreted with caution because the relatively small sample size

and retrospective design may lead to selection bias for treatment. Prospective, multi-

institution randomized trials are urgently needed to determine the optimal treatment

combination or sequence. The BRAIN study indicated that, in patients with EGFR-

mutant NSCLC and multiple brain metastases, icotinib was more recommended as a

first-line therapeutic option over WBI treatment[12]. It is recommended that through

the use of highly active targeted therapies, WBRT can be safely postponed in patients

with EGFR mutation and BM[30]. However, the optimal sequences between EGFR

TKI and RT are still controversial.

We also found that the administration of chemotherapy on the basis of EGFR TKIs

can significantly improve the survival and was a prognostic predictor. Accordingly,

chemotherapy could achieve better systemic disease control. In our study, 147 patients

received chemotherapy, with 97 (66.0%) receiving pemetrexed-based chemotherapy.

It is reported that some drugs might, to some extent, penetrate the blood-brain barrier

(BBB) and gain intracranial control. Barlesi et al. previously demonstrated that

pemetrexed-based chemotherapy had the greatest activity, as well as a favorable

safety profile, in managing NSCLC patients with inoperable BM[31]. It should be

noted that this study did not observe whether the adoption of chemotherapy on the

basis of EGFR TKIs would bring more adverse effect.

The results of our study confirmed the DS-GPA index remains a robust tool and was

useful for estimating survival in EGFR-mutant patients with BM. However, the Lung-

molGPA index updated by Sperduto et al did not appear superior when compared to

DS-GPA in the gene-specific NSCLC patients with BM in this study. Perhaps a more

accurate and user-friendly tool could be developed for patients with specific

oncogenic driver genes.

This study is limited by its retrospective nature. Because it is a single-institutional

study, there may have been bias in choosing patients for enrollment. Therefore, the

results reported here are not entirely representative of a large sample population.

Another limitation of this study is that follow-up data on toxicities, cognitive

impairment and quality of life were lacking; therefore, we were unable to analyze

these factors.

In conclusion, this study provided real-world evidence for the survival and prognosis

of EGFR-mutant NSCLC patents with BM. Performance status (KPS≥70), absence of

ECM, the administration of local treatment or chemotherapy might all predict superior

OS in EGFR-mutant NSCLC patients who develop brain metastases. While the DS-

GPA and Lung-molGPA indexes were still robust tools, we propose a more accurate

and user-friendly tool that applies to patients including specific gene status and BM.

Further studies with large sample sizes are warranted.

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Table 1. Baseline characteristics

Characteristic n (%)

Age (30-79 years)≤65 years old 224 (85.8%)>65 years old 37 (14.2%)GenderMale 106 (40.6%)Female 155 (59.4%)Smoking historySmoker 72 (27.6%)Nonsmoker 189 (72.4%)Performance statusKPS<70 74 (28.4%)KPS≥70 187 (71.6%)Histology n (%)Adenocarcinoma 240 (92.0%)Others 21 (8.0%)Number of BM≤3 175 (67.0%)

>3 86 (33.0%)ECMYes 117 (44.8%)No 144 (55.2%)Symptomatic BMWith 147 (56.3%)Without 114 (43.7%)Synchronous BMYes 189 (72.4%)No 72 (27.6%)EGFR mutationExon 19 deletion 138 (52.9%)L858R 90 (34.5%)Others 33 (12.6%)Intracranial local therapyYes 195 (74.7%)No 66 (25.3%)Chemotherapy Without 114 (43.7%)With 147 (56.3%)DS-GPA score

0-0.542

(16.1%)

1-1.5107

(41.0%)

2-2.586

(33.0%)

≥326

(10.0%)

Lung-molGPA score0-1 7 (2.7%)

1.5-271

(27.2%)

2.5-3125

(47.9%)

≥3.558

(22.2%)

Abbreviations: BM, brain metastases; DS-GPA, diagnosis-specific graded prognostic

assessment; ECM, extracranial metastases; EGFR, epidermal growth factor receptor;

KPS, Karnofsky performance score; TKI, tyrosine kinase inhibitor.

Table 2. Univariable and Multivariable Analyses of Covariables Associated With OSUnivariate analysis Multivariate analysis-reduced

Variables Hazar

d ratio

95% CI p value Hazard

ratio

95% CI p value

Age (>65 y/o) 1.579 1.052-2.369 .025 1.436 0.949-2.172 .087

Gender (male) 1.141 0.846-1.540 .384

Smoking history (smoker) 1.077 0.781-1.485 .649

KPS≥70 0.626 0.457-0.859 .003 0.639 0.455-0.897 .010

BM numbers >3 0.946 0.687-1.302 .729

ECM 1.744 1.287-2.362 .000 1.733 1.256-2.391 .001

EGFR mutation 1.024 0.840-1.247 .343

Intracranial local therapy 0.546 0.392-0.761 .000 0.607 0.430-0.857 .005

Chemotherapy 0.598 0.442-0.808 .001 0.629 0.455-0.870 .005

DS-GPA score 0.675 0.558-0.818 .000

Lung-molGPA score 0.667 0.551-0.807 .000

Abbreviations: BM, brain metastases; DS-GPA, diagnosis-specific graded prognostic

assessment; ECM, extracranial metastases; EGFR, epidermal growth factor receptor;

KPS, Karnofsky performance score; OS, overall survival.

Figure 1. Patient selection and exclusion criteria.

Abbreviations: NSCLC, non-small cell lung cancer; BM, brain metastases; EGFR,

epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; KPS, Karnofsky

performance score.

Figure 2. Kaplan-Meier curve illustrating OS of EGFR-mutant NSCLC patients with

brain metastases showed a median OS (months from start of brain metastasis) of 23.0

months (95% CI: 20.0-26.0).

Figure 3. Kaplan-Meier analysis comparing overall survival in patients based on the

DS-GPA and Lung-molGPA indexes. (A): For the DS-GPA, patients with a score of

more than 3 had the longest median OS, 42.0 months (95% CI: 16.0-68.8), followed

by those with a score of 2-2.5 (median OS=27.0 months; 95% CI: 22.6-31.4), those

with a score of 1-1.5 (median OS=17.7 months; 95% CI: 14.4-21.0), and those with a

score of 0-0.5 (median OS=16.0 months; 95% CI: 8.6-23.4). (B): For the Lung-

molGPA, patients with a score of more than 3.5 had the longest median OS, 32.0

months (95% CI: 21.4-42.6), followed by those with a score of 2.5-3 (median

OS=23.7 months; 95% CI: 18.9-28.5), those with a score of 1.5-2 (median OS=16.0

months; 95% CI: 11.5-20.6), and those with a score of 0-1 (median OS=15.0 months;

95% CI: 2.2-27.8).

Figure 4. Kaplan-Meier analysis showing survival based on different factors for

NSCLC: (A)age (mOS: 23.7 vs 18.8 months, p=0.025), (B)KPS (mOS: 16.0 vs 24.9

months, p=0.003), (C)ECM (mOS: 32.0 vs 19.7 months, p=0.000), (D)BM numbers

(mOS: 22.7 vs 23.6 months, p=0.729), (E)intracranial local therapy (mOS: 16.0 vs

24.9 months, p=0.000), (F)chemotherapy (mOS: 16.5 vs 28.0 months, p=0.001)